It is generally accepted that one of the immune system's major roles is that of immunological surveillance to destroy abnormal cells. There has been extensive research to determine the defect in immune function that allows a tumor cell to escape this surveillance and subsequently develop into a viable tumor. It has been postulated that tumors develop because of general immune suppression. However, if general immune suppression occurs, only certain types of neoplastic disorders usually develop, such as those involving the lympho-reticular system. It has been suggested that prostaglandins play a significant role in the regulation of the local immune response, as well as carcinogen activation and tumor initiation. Therefore, more recent studies have focused on localized immune suppression. Experimental work has shown that, during the development of tumors, host macrophage are triggered to produce high levels of prostaglandin E.sub.2 (PGE.sub.2). Monocytes, lymphoid cells, and many tumor cells have also been shown to produce high levels of prostaglandins. The immunosuppressive effects of PGE.sub.2 include the inhibition of: T and B lymphocyte proliferation, lymphokine production, cytotoxicity of natural killer (NK) cells, effector functions of T-cells, B-cells, and macrophages, and generation of cytotoxic T lymphocytes and lymphokine-activated killer (LAK) cells.
Studies using prostaglandin synthesis inhibitors, like non-steroidal anti-inflammatory drugs (NSAID), have provided further evidence for the role of prostaglandins in mediating immunosuppression. Considerable evidence further suggests that NSAIDs may have an important role in chemoprevention. The use of NSAIDs, such as aspirin, indomethacin, piroxicam, and fluorbiprofen, has been shown effective in reducing or inhibiting tumor growth and bone metastasis.
PCT Patent Publication WO93/16732 (Falk, et al.) teaches compositions, in the form of a gel or cream, which are suitable for topical application comprising pharmaceutical excipients (1-5%, by weight) and an effective amount of hyaluronic acid (1-3%, by weight) sufficient to transport the drug to a site in the skin including epidermis, or exposed tissue of a disease or condition. The pharmaceutical excipients include nonsteroidal anti-inflammatory drugs selected from the group comprising diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac, ibuprofen, piroxicam, propionic acid derivatives, acetylsalicylic acid, and fiunixin. Other pharmaceutical excipients include anti-cancer drugs selected from the group comprising Novantrone and 5-Fu (Fluorouracil). The compositions are claimed to be effective in the treatment of diseases and/or conditions selected from the group comprised of at least one basal cell carcinoma, actinic keratoses lesions, fungal lesions, "liver" spots, squamous cell tumors, metastatic cancer of the breast to the skin, primary and metastatic melanoma in the skin, genital warts, cervical cancer, Human Papilloma Virus of the cervix, psoriasis, corns of the feet, and hair loss on the head of pregnant women.
Falk, et al. postulates that the use of an NSAID prevents the enzymatic production of prostaglandins, which block macrophage and Natural Killer (NK) cell functions in the local anti-tumor immune response. They suggest that the hyaluronic acid enhances the activity of prostaglandin synthesis inhibition and reduces any side effects that are associated with the use of the NSAID. Hyaluronic acid passes between the cells to the areas of trauma and/or pathology, transporting the NSAID with it, until the space between the cells is saturated. This allows the drug to remain at the areas of trauma and/or pathology for prolonged periods. The composition is subsequently cleared through tile lymphatic system.
Worldwide, oral carcinoma is one of the most prevalent cancers. Cancers of the oral cavity and oropharynx account for approximately 3% of all cancers diagnosed in the United States each year. Approximately 95% of all oral cancers occur in people older than 40 years of age and represents about 4% of total body cancers in males and about 2% in women. The survival rate is about 50% and deaths due to oral and oropharyngeal cancers represent approximately 2% of the total cancer related deaths in men and 1% in women, making it one of the 10 most common causes of death. The majority of oral cancers are squamous cell carcinomas and most commonly involve the tongue, oropharynx, and floor of the mouth, with the lips, gingiva, dorsal tongue, and palate being less common sites.
Surgery and/or radiation therapy are the current treatments of choice for oral cancers, such as squamous cell carcinoma. Chemotherapeutic agents, such as methotrexate, bleomycin, cisplatin, and 5-Fluorouracil, may reduce tumor bulk and delay metastasis, but the profound morbidity associated with this type of treatment may not justify their use as the only treatment modalities. Therefore, most current chemotherapeutic agents are used primarily as adjunctive therapy to surgery and/or radiation therapy in advanced cases of disease.
Patients with squamous cell carcinoma often have deficiencies in cellular and humoral immune functions. Immunosuppression observed in these patients is variable but appears to be the greatest at local and regional levels and several studies have demonstrated significant elevations of PGE.sub.2 in tumor specimens from these patients.
It is an object of the present invention to provide a topical prevention and treatment of primary and/or recurring squamous cell carcinoma of the oral cavity and oropharynx using an NSAID, alone or as an adjunct to surgery and/or radiation therapy.
It is also an object of the present invention to provide a topical prevention and treatment of primary and/or recurring squamous cell carcinoma of the oral cavity and oropharynx using ketorolac, alone or as an adjunct to surgery and/or radiation therapy.
It is a further object of the present invention to provide such treatments which result in a minimal systemic (blood) concentration of ketorolac.
All percentages and ratios used herein are by weight, and all measurements made at 25.degree. C., unless otherwise specified.